Therapeutic activity of neutralizing monoclonal antibodies targeting hepatoma-derived growth factor in cancer xenograft models

2517 Background: Hepatoma-derived growth factor (HDGF) is a mitogen for endothelial cells, vessel smooth muscle cells, fibroblasts, as well as some epithelial cells. It is overexpressed in a number of human cancers and its overexpression in tumors strongly correlates with tumor progression, recurrence, and metastasis. We recently showed that down-regulation of HDGF in lung cancer cells reduces tumorigenecity in both in vitro cell and in vivo animal models suggesting HDGF may be of a therapeutic target for cancer. Methods: Recombinant HDGF was used to develop a panel of monoclonal antibodies specifically bind to HDGF. Four antibodies were tested for their therapeutic activity in lung and pancreatic cancer xenograft models. The monoclonal antibodies were administered 250μg/animal (5 mice per group) every 3 days IP when the subcutaneous tumors reached approximately 50 mm3. Results: Two antibodies (C1 and H3) exhibited significant therapeutic activity in A549 lung cancer model whereas H3 also showed a therapeutic effect in MiaPaca-2 pancreatic cancer model. No sign of toxicity in the living animals and histology of major organs were observed in the antibody treated animals. In the A549 model, the mean tumor burden was 960 mm3 for control-IgG treated mice 22 days after tumor inoculation, whereas the mean tumor burdens were 224 mm3 for C1 and 266 mm3 for H3 treated mice (P < 0.05) respectively. In the MiaPaca-2, the mean tumor burden was 994 mm3 for control-IgG treated mice 21 days after tumor inoculation in contrast to 345 mm3 for H3 treated mice (P < 0.05). Consistent with known biologic functions of HDGF, our early morphologic and biomarker analyses suggest that H3 may neutralize tumor cell released HDGF resulting in disruption of tumor stroma and extracellular matrix structures. Conclusions: HDGF is a novel therapeutic target for multiple human cancers and neutralizing monoclonal antibodies targeting HDGF are effective in treating lung and pancreatic cancers in animal models. (Supported by DoD grant DAMD17–01–1-01689–1) No significant financial relationships to disclose.

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Targeted Therapies for Pancreatic Cancer

Cancers ◽

10.3390/cancers10020036 ◽

2018 ◽

Vol 10 (2) ◽

pp. 36 ◽

Cited By ~ 30

Author(s):

Idoroenyi Amanam ◽

Vincent Chung

Keyword(s):

Lung Cancer ◽

Pancreatic Cancer ◽

Overall Survival ◽

Monoclonal Antibodies ◽

Small Molecule ◽

Targeted Therapies ◽

Median Overall Survival ◽

The Third ◽

One Year ◽

Targeted Approach

Pancreatic cancer is the third leading cause of cancer related death and by 2030, it will be second only to lung cancer. We have seen tremendous advances in therapies for lung cancer as well as other solid tumors using a molecular targeted approach but our progress in treating pancreatic cancer has been incremental with median overall survival remaining less than one year. There is an urgent need for improved therapies with better efficacy and less toxicity. Small molecule inhibitors, monoclonal antibodies and immune modulatory therapies have been used. Here we review the progress that we have made with these targeted therapies.

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Immunotherapy with Monoclonal Antibodies in Lung Cancer of Mice: Oxidative Stress and Other Biological Events

Cancers ◽

10.3390/cancers11091301 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1301 ◽

Cited By ~ 3

Author(s):

Jun Tang ◽

Daniel Ramis-Cabrer ◽

Xuejie Wang ◽

Esther Barreiro

Keyword(s):

Oxidative Stress ◽

Lung Cancer ◽

Monoclonal Antibodies ◽

Experimental Models ◽

Tumor Burden ◽

Sirtuin 1 ◽

Future Research ◽

Ki 67 ◽

Cell Counts ◽

Reduce Tumor Burden

Background: Lung cancer (LC) is a major leading cause of death worldwide. Immunomodulators that target several immune mechanisms have proven to reduce tumor burden in experimental models through induction of the immune microenvironment. We hypothesized that other biological mechanisms may also favor tumor burden reduction in lung cancer-bearing mice treated with immunomodulators. Methods: Tumor weight, area, T cells and tumor growth (immunohistochemistry), oxidative stress, apoptosis, autophagy, and signaling (NF-κB and sirtuin-1) markers were analyzed (immunoblotting) in subcutaneous tumor of BALB/c mice injected with LP07 adenocarcinoma cells treated with monoclonal antibodies (CD-137, CTLA-4, PD-1, and CD-19, N = 9/group) and non-treated control animals. Results: Compared to non-treated cancer mice, in tumors of monoclonal-treated animals, tumor area and weight and ki-67 were significantly reduced, while T cell counts, oxidative stress, apoptosis, autophagy, activated p65, and sirtuin-1 markers were increased. Conclusions: Immunomodulators elicited a reduction in tumor burden (reduced tumor size and weight) through decreased tumor proliferation and increased oxidative stress, apoptosis, autophagy, and signaling markers, which may have interfered with the immune profile of the tumor microenvironment. Future research should be devoted to the elucidation of the specific contribution of each biological mechanism to the reduced tumor burden.

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Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Nature Communications ◽

10.1038/s41467-020-18442-4 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Rong Wang ◽

Tadaaki Yamada ◽

Kenji Kita ◽

Hirokazu Taniguchi ◽

Sachiko Arai ◽

...

Keyword(s):

Lung Cancer ◽

Growth Factor ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Adaptor Proteins ◽

Small Population ◽

Survival Signal ◽

Epidermal Growth ◽

Xenograft Models

Abstract Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.

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Personalized Medicine in Non–Small-Cell Lung Cancer: Is KRAS a Useful Marker in Selecting Patients for Epidermal Growth Factor Receptor–Targeted Therapy?

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.4365 ◽

2010 ◽

Vol 28 (31) ◽

pp. 4769-4777 ◽

Cited By ~ 178

Author(s):

Patrick J. Roberts ◽

Thomas E. Stinchcombe ◽

Channing J. Der ◽

Mark A. Socinski

Keyword(s):

Colorectal Cancer ◽

Lung Cancer ◽

Monoclonal Antibodies ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Small Cell ◽

Small Cell Lung ◽

Kras Mutations ◽

Mutational Status ◽

Epidermal Growth

In patients with metastatic colorectal cancer, the predictive value of KRAS mutational status in the selection of patients for treatment with anti–epidermal growth factor (EGFR) monoclonal antibodies is established. In patients with non–small-cell lung cancer (NSCLC), the utility of determining KRAS mutational status to predict clinical benefit to anti-EGFR therapies remains unclear. This review will provide a brief description of Ras biology, provide an overview of aberrant Ras signaling in NSCLC, and summarize the clinical data for using KRAS mutational status as a negative predictive biomarker to anti-EGFR therapies. Retrospective investigations of KRAS mutational status as a negative predictor of clinical benefit from anti-EGFR therapies in NSCLC have been performed; however, small samples sizes as a result of low prevalence of KRAS mutations and the low rate of tumor sample collection have limited the strength of these analyses. Although an association between the presence of KRAS mutation and lack of response to EGFR tyrosine kinase inhibitors (TKIs) has been observed, it remains unclear whether there is an association between KRAS mutation and EGFR TKI progression-free and overall survival. Unlike colorectal cancer, KRAS mutations do not seem to identify patients who do not benefit from anti-EGFR monoclonal antibodies in NSCLC. The future value of testing for KRAS mutational status may be to exclude the possibility of an EGFR mutation or anaplastic lymphoma kinase translocation or to identify a molecular subset of patients with NSCLC in whom to pursue a drug development strategy that targets the KRAS pathway.

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